Activation of acetyl-coenzyme A carboxylase is involved in Taxol-induced ovarian cancer cell death

Acetyl-coenzyme A carboxylase (ACC) is an attractive target for research into the treatment of a variety of human diseases, including diabetes, obesity and cancer. Mounting evidence suggests that the inhibition of ACC induced of cancer cell apoptosis. However, whether the inhibition of ACC regulates apoptosis in CaOV3 cancer cells has yet to be addressed. This study investigated the cytotoxic mechanism of action of ACC inhibition. Results showed that 5-(tetradecyloxy)-2-furoic acid (TOFA), an ACC inhibitor, enhanced Taxol-induced CaOV3 human ovarian cancer cell apoptosis. Notably, when TOFA was administered as a monotherapy, it induced CaOV3 cell apoptosis. Pre-treatment with the EGFR inhibitor PD153035 was found to markedly enhance ACC phosphorylation, whereas AMP-activated protein kinase (AMPK) activator AICAR was found to marginally enhance ACC phosphorylation. Taken together, the data showed ACC is a potential novel molecular target of Taxol. Additionally, ACC inhibition partially contributed to the cytotoxic effect of Taxol in ovarian cancer cells.     

Adenoid Cystic Carcinoma Metastatic to the Dura: Report of Two Cases

Adenoid cystic carcinoma (ACC) originating in the salivary and lacrimal glands usually spreads to the intracranial space by following cranial nerves into the cavernous sinus, temporal bone and cerebellopontine angle. We present two cases in which ACC metastasized extensively to the dura, suggesting that ACC has an affinity for the dura. Case 1, a 43-year-old man, was operated on 12 years earlier for invasive ACC of the right palate. He experienced recurrence of the tumor in the left cavernous sinus and sella, and extensive involvement of the dura of both right and left temporal fossae. Case 2, a 33-year-old woman, had spread of ACC to the right convexity dura and tentorium after undergoing a resection of a left-sided ACC tumor of the lacrimal gland two years earlier. Both patients underwent multiple resections and radiation treatment. Extensive, multifocal, bilateral spread of ACC to the dura in both cases indicates that ACC has an affinity for the dura.     

Genes associated with early development, apoptosis and cell cycle regulation define a gene expression profile of adenoid cystic carcinoma

Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by indolent yet relentless growth that exhibits inherent resistance to systemic chemotherapy, surgical salvage and conventional radiotherapy. We used microarray analysis to characterize gene expression changes associated with ACC. Eight ACC patient specimens were compared with normal parotid gland tissue and the ACC3 cell line. Differentially expressed genes were identified (512 total) using supervised analysis methods and functional categories assigned using OntoExpress. Genes associated with morphogenesis, neurogenesis, proliferation and apoptosis characterized ACC tumors. Genes associated with saliva production and immune response characterized normal parotid tissues while the ACC3 cell line expressed genes primarily associated with proliferation, chromosome maintenance and the cell cycle. These results demonstrate that ACC tumors express genes associated with early developmental processes including morphogenesis and neurogenesis implicating oncogenic events that result in dedifferentiation of normal salivary glands.     

Unfavorable clinical implications for hypermethylation of RUNX3 in patients with salivary gland adenoid cystic carcinoma

To elucidate the potential etiological role of RUNX3 in the development of salivary gland adenoid cystic carcinoma (ACC), we analyzed the methylation status of RUNX3 in a series of 114 ACC tissues and 3 ACC cell lines. Results showed that the methylated rate of RUNX3 was 50.9 and 3.5% in the 114 ACC samples and the corresponding normal salivary glands, respectively, achieving a significant difference (P<0.001). There was a significant correlation between RUNX3 methylation and various clinicopathological parameters of ACCs, such as perineural invasion, lymph node involvement, T-stage and distant metastasis (P<0.001). RUNX3 methylation was a significant predictor of the 5-year disease-free survival in ACC patients after surgery. Partial methylation was found in all 3 ACC cell lines, and the reactivation and more potent expression of RUNX3 was induced by 5-triazole-2-deoxycytidine. Our findings indicate that RUNX3 methylation may occur as a common event in the development of ACC and that methylation may be a major mechanism for inactivation of RUNX3 in ACC.     

Protein expression profiling identifies maspin and stathmin as potential biomarkers of adenoid cystic carcinoma of the salivary glands

Adenoid cystic carcinoma (ACC) is one of the most common malignant tumors of the salivary glands. It tends to grow slowly but is associated with a poor prognosis compared to other malignant salivary gland tumors. To identify specific markers of ACC, we examined protein expression profiling in ACC xenograft and normal salivary glands (NSG) using fluorescent 2-dimensional differential in-gel electrophoresis (2-D-DIGE), an emerging technique for comparative proteomics, that improves the reproducibility and reliability of differential protein expression analysis between the samples. To identify the proteins, matrix-assisted laser desorption/ionization time-of-flight peptide mass fingerprinting was carried out. Using these strategies, we detected 4 upregulated proteins and 5 downregulated proteins in ACC xenograft. Maspin and stathmin were selected for further analyses. Western blotting and immunohistochemical staining showed a higher expression of these proteins in ACC xenograft and clinical ACC tissue compared to NSG. Furthermore, Expression of these proteins was correlated with the histologic grading of ACC (n = 10). Therefore, our data indicate that maspin and stathmin may be not only useful biomarkers of ACC but also markers of biologic behavior in this tumor.     

酪氨酸激酶B在涎腺腺样囊性癌中的表达及与嗜神经侵袭的关系

目的检测酪氨酸激酶B(TrkB)在涎腺腺样囊性癌(ACC)的表达情况，探讨TrkB与ACC嗜神经侵袭的关系。方法研究对象为28例ACC，3例正常腮腺，3例正常颌下腺，3例正常舌下腺及5例涎腺腺泡细胞癌标本，采用免疫组织化学及图像分析法对组织切片中的TrkB进行检测。结果以病理学表现为标准，28例ACC中的嗜神经侵袭率为46．4％(13／28)，TrkB阳性率为92．8％(26／28)，存在嗜神经现象组中TrkB表达水平明显高于未见嗜神经现象组(P=0．001)。TrkB的表达在正常大涎腺的导管细胞为阳性，而在腺泡细胞癌胞浆内均为阴性。结论TrkB可能作为ACC嗜神经侵袭的生物学标志物。TrkB表达的增高可能是ACC嗜神经侵袭的机理之一。     

A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets

MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.     

食管癌患者外周血补体抑制水平的检测

采用一种灵敏的补体溶血抑制实验，测定了51例食管病变及37例健康人血清中的补体抑制水平。结果显示，正常对照组与食管良性病变组之间，血清补体抑制水平差异不显著；食管癌组的补体抑制水平明显高于健康人及食管良性病变组；同正常组比较，不同病期食管癌患者血清补体抑制率均明显升高。因此认为，血清中补体抑制水平的升高，有可能是肿瘤病人产生免疫抑制的原因之一。     

Polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma: a review and comparison of immunohistochemical markers

Polymorphous low-grade adenocarcinoma (PLGA) and adenoid cystic carcinoma (ACC) have several overlapping histological patterns, including cribriform, tubular and solid patterns. The overlapping clinicopathological features of PLGA and ACC may result in a diagnostic pitfall. ACC has a much worse prognosis than PLGA, making differentiation important for therapeutic and prognostic purposes. Histopathological features remain the most reliable criteria to distinguish between these two tumours. Although PLGA and ACC have many features in common, PLGA is uncommon in the major salivary glands. Histopathological distinction is therefore mainly a problem in tumours of minor salivary gland origin where small biopsies often contribute to diagnostic difficulties. This paper reviews studies which have utilised several immunohistochemical markers in attempts to distinguish between PLGA and ACC, and also studies which have focussed on the two tumours individually. The potential discriminating value of immunohistochemistry between cases of PLGA and ACC still remains controversial.     

S-100和NCAM在腺样囊性癌组织中的表达及意义

  目的  分析腺样囊性癌(adenoid cystic carcinoma, ACC)的临床病理特点, 观察雪旺细胞标记物S-100和神经细胞粘附分子(neural cell adhesion molecule, NCAM)在ACC中的表达, 探讨S-100和NCAM与ACC嗜神经侵袭性的关系。  方法  对天津医科大学口腔医院42例ACC病例应用免疫组织化学方法检测S-100和NCAM在ACC中的表达, 并探讨其相关性。  结果  S-100在ACC嗜神经组阳性表达率80.0%明显高于非嗜神经组33.3%(P=0.011)。NCAM在嗜神经和非嗜神经侵袭组ACC中的阳性表达差异无统计学意义。S-100与NCAM在ACC中的阳性表达无明显相关性(P > 0.05)。  结论  S-100蛋白的表达与ACC的嗜神经现象密切相关, 在管状型中的表达明显高于充实型, 与肿瘤细胞分化具有一定相关性。NCAM蛋白的表达与ACC的嗜神经现象无统计学相关性, 与S-100蛋白的表达亦无明显相关。      

microRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma

Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7–5p (miR-7) reduces cell proliferation in vitro and induces G₁ cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle (^EGFREDV^TM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDV^TM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.     

c-kit蛋白和Ki-67表达在涎腺基底细胞腺瘤和腺样囊性癌诊断中的意义

 目的　探讨原癌基因c-kit和细胞核增殖抗原Ki-67的表达在涎腺基底细胞腺瘤和腺样囊性癌诊断中的意义。方法　应用免疫组织化学方法检测18例基底细胞腺瘤和42例腺样囊性癌标本中瘤细胞c-kit和Ki-67的表达。结果　18例基底细胞腺瘤和42例腺样囊性癌中c-kit的表达率分别为72.2 %（13／18）和83.3 %（35／42）,两者差异无统计学意义（χ2＝0.11,P＞0.05）;18例基底细胞腺瘤和42例腺样囊性癌中Ki-67的平均表达率分别为（3.72±1.41）%和（23.81±10.19）%,两者差异有统计学意义（t＝14.145,P＜0.01）。结论　原癌基因c-kit表达对涎腺基底细胞腺瘤和腺样囊性癌的鉴别诊断无意义, Ki-67 对两者鉴别诊断有意义。     

Adenoid cystic carcinoma of the esophagus. A clinicopathologic study of three cases.

In a group of 245 cases of primary carcinoma of the esophagus the authors found three cases of adenoid cystic carcinoma (ACC). Clinical and pathologic data of those patients (one female and two male; age range, 49-74 years) were analyzed. Tumors were localized in the middle third of the esophagus. One patient lived 15 months after surgery. Another is a case of early ACC who has been living 4.5 years after surgery and is without specific symptoms. The third patient had not had surgery and died 13 months after the onset of dysphagia. An autopsy showed only a locally invasive tumor growing into the surroundings of the esophagus, and regional lymph node metastases without distant parenchymal metastases. These findings support pathologic and biologic similarities between ACC of the esophagus and ACC of the salivary glands. There are synchronous tumors of the esophagus and the vital localization which makes the prognosis of ACC of the esophagus worse than ACC of the salivary glands.     

Clinical characteristics and surgical outcomes of resectable acinar cell carcinoma of the pancreas-propensity score matching analysis with pancreatic ductal adenocarcinoma

BackgroundSurgical resection is recommended for patients with resectable acinar cell carcinoma (ACC). The aim of this study was to investigate the clinical characteristics and surgical outcomes of resectable ACC in comparison to pancreatic ductal adenocarcinoma (PDAC).MethodA retrospective analysis was performed on all patients who consecutively underwent radical resection with pathologically confirmed ACC and PDAC from December 2011 to December 2018. Clinicopathologic characteristics and follow-up information were analyzed. A 1:3 propensity score matching (PSM) method was used to minimize the bias between ACC and PDAC.ResultsA total of 26 patients with ACC and 1351 with PDAC were included. Compared to PDAC, ACC tended to be larger (4.5 vs. 3.0 cm; p < 0.001) and more frequently located in the pancreatic body/tail (61.5% vs. 36.6%, p = 0.009), with lower total bilirubin levels, lower neutrophil lymphocyte ratio (NLR) levels and lower carbohydrate antigen 19-9 (CA19-9) levels and carcinoembryonic antigen (CEA) levels. There was no difference in postoperative morbidities in patients with ACC and PDAC. The median OS and RFS were longer in ACC when compared to PDAC (OS: 43.5 mo vs. 19.0 mo, p = 0.004; RFS: 24.5 mo vs. 11.6 mo, p = 0.023). After the 1:3 PSM, ACC remained to be a better histological type for OS (p = 0.024), but had comparable RFS with PDAC (p = 0.164).ConclusionPatients with ACC after radical resection had better OS than that with PDAC. However, ACC is also an aggressive tumor with a similar trend of RFS with PDAC after the matching, necessitating the multidisciplinary treatment for resectable ACC disease.     

Establishment of patient-derived xenograft models of adenoid cystic carcinoma to assess pre-clinical efficacy of combination therapy of a PI3K inhibitor and retinoic acid

Due to the difficulties and long periods of establishment, preclinical animal models of adenoid cystic carcinoma (ACC) are scarce but imperative. The researches involving molecular features and therapeutic targets of ACC require an integrated group of preclinical animal models which can credibly retain the heterogeneity of this tumor. Currently chemotherapies and targeting therapies have modest efficacy in ACC and the overall response rate is rather low. Therefore, novel therapeutic regimen of ACC is urgently needed and remains a major clinical challenge. We transplanted a group of tumor samples from human salivary ACC into immunodeficient mice to establish patient-derived xenografts (PDXs). Patient tumors and their matched PDXs were conducted histological analyses, whole-exome sequencing (WES) and RNA-seq respectively. 13 PDXs were successfully established from 34 ACC, involved in 3 histological types, including cribriform, tubular, and solid. These ACC PDXs generally reflected the histopathological and molecular features of their corresponding original tumors. MYB/MYBL1-NFIB fusion (53.85%) and high-frequency mutation genes, such as KDM6A, KMT2C, KMT2D, NOTCH1, NOTCH2, SMARCA4 and PIK3CA were mainly conserved in PDXs. Guided by the genetic alterations, the efficiencies of retinoic acid (RA) and a PI3K inhibitor were evaluated in ACC PDX models harboring both MYB fusion and PIK3CA amplification/mutation. Combination treatment of the PI3K inhibitor and RA demonstrated remarkable inhibition of tumors in PDXs harboring both PIK3CA mutation/amplification and MYB-NFIB fusion gene in vivo and in vitro. In this study, we displayed the morphologically and genetic featured PDXs which recapitulated the heterogeneity of original ACC tumors, indicating that the models could be used as a platform for drug screening for therapy response. The feasibility of combination treatment approaches for dual targets were confirmed, providing new regimens for personalized therapies in ACC.     

Adenoid cystic carcinoma of the head and neck--a clinical study of 27 cases

Adenoid cystic carcinoma (ACC) is frequently seen in the salivary glands, but may occur at other sites in the head and neck. We report 27 patients with ACC treated at the Department of Otorhinolaryngology, Mie University School of Medicine, for 15 years. The survival rate dropped from 78% at five years to 36% at 10 years. This suggests that the long-term prognosis of ACC is poor. According to Batsakis, we classified ACC according to histopathology and emphasize that the solid cellular pattern had the worst prognosis.